| Distribution of a 20-mer phosphorothioate oligonucleotide, CGP69846A (ISIS 5132), into airway leukocytes and epithelial cells following intratracheal delivery to brown-norway rats. | |
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MedLine Citation:
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PMID: 10554095 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: To evaluate the pulmonary distribution of CGP69846A (ISIS 5132), a phosphorothioate oligonucleotide, following intra-tracheal (i.t.) instillation into Brown-Norway rats. METHODS: The pharmacokinetic profile of [3H]-CGP69846A was investigated following i.t. instillation into both naive and inflamed airways of Brown-Norway rats. The cellular distribution was determined using autoradiography, immunohistochemistry and flow cytometry/fluorescence microscopy, in inflamed airways. RESULTS: CGP69846A displayed a dose-dependent lung retention following i.t. administration which was unaffected by local inflammation. Autoradiography and immunohistochemistry showed distribution to alveolar macrophages, eosinophils, bronchial and tracheal epithelium and alveolar cells. Studies with [FITC]-CGP69846A demonstrated a preferential association of oligonucleotide with leukocytes in bronchial lavage fluid of: macrophages > eosinophils = neutrophils >> lymphocytes. CONCLUSIONS: The dose-dependency of lung retention together with cell-specific uptake suggests that the lung can be used as a local target for antisense molecules with potentially minimal systemic effects. Furthermore, the preferential targeting of macrophages and the airway epithelium by oligonucleotides may represent rational cellular targets for antisense therapeutics. |
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Authors:
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H Danahay; J Giddings; R A Christian; H E Moser; J A Phillips |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Pharmaceutical research Volume: 16 ISSN: 0724-8741 ISO Abbreviation: Pharm. Res. Publication Date: 1999 Oct |
Date Detail:
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Created Date: 1999-12-23 Completed Date: 1999-12-23 Revised Date: 2003-11-14 |
Medline Journal Info:
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Nlm Unique ID: 8406521 Medline TA: Pharm Res Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 1542-9 Citation Subset: IM |
Affiliation:
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Novartis Horsham Research Centre, Horsham, West Sussex, UK. henry.danahay@pharma.novartis.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Autoradiography Bronchoalveolar Lavage Fluid Epithelial Cells / metabolism* Fluorescein-5-isothiocyanate / metabolism Immunohistochemistry Intubation, Intratracheal Leukocytes / metabolism* Lung / cytology, metabolism Microscopy, Fluorescence Oligodeoxyribonucleotides, Antisense / metabolism* Oligoribonucleotides, Antisense / administration & dosage, pharmacokinetics* Rats Rats, Inbred BN Respiratory System / cytology, metabolism Spectrophotometry, Ultraviolet Thionucleotides / metabolism* Tissue Distribution |
| Chemical | |
Reg. No./Substance:
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0/ISIS 5132; 0/Oligodeoxyribonucleotides, Antisense; 0/Oligoribonucleotides, Antisense; 0/Thionucleotides; 3326-32-7/Fluorescein-5-isothiocyanate |
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